Improving the efficacy and reducing the toxicity of chemotherapeutics using a nanoparticle drug-delivery system
Conventional chemotherapeutics, including doxorubicin, have significant dose limiting toxicities. While chemotherapeutics are frequently successful at halting or reversing tumor progression, their use is hampered by toxicity within healthy tissues of the body. Packaging clinically approved drugs into nanoscale delivery vehicles (10–100 nm diameter) is of particular interest for cancer therapy, as numerous studies have shown that objects within this size range accumulate within solid tumors owing to the enhanced permeability and retention effect. However, there is a need in the field for drug-polymers with improved pharmacokinetic and biodistribution properties that increase therapeutic efficacy while reducing toxicity.
Duke inventors have reported a low-toxicity nanoparticle drug delivery system intended to improve the efficacy of hydrophobic small-molecule drugs. These are artificial recombinant chimeric polypeptides (CPs) that spontaneously self-assemble into sub-100-nm-sized, near-monodisperse nanoparticles on conjugation of diverse hydrophobic molecules. The polypeptides exhibit lower critical solution temperature phase behavior, enabling them to form gel-like depots that increase the half-life of their cargo. When used to deliver hydrophobic chemotherapeutics such as doxorubicin and paclitaxel in mouse cancer models, CP nanoparticles demonstrated a higher maximum tolerated dose than free drug and induced significantly greater tumor regression than free drug. Notably the CP-paclitaxel nanoparticle outperformed Abraxane at an equitoxic dose in multiple mouse models.
- Degrades into non-toxic components that enable clearance from the body without adverse toxicity
- The use of recombinant DNA methodology provides a simpled mechanism for controlling particle diameter, degree of drug loading and incorporation of other biologically active peptides
- Can be applied to a range of hydrophobic drugs in a simple two-step synthesis
- Animal studies demonstrated improved efficacy using doxorubicin and paclitaxel